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Vol 16, No 5 (May 2002)

Current Management of Childhood Ependymoma

Thomas E. Merchant, DO, PhD Associate Member and Clinical Director, Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee Introduction Prognostic Factors Treatment Rationale for Future Studies Current Recommendations References Reviewers' Comments: Kenneth J. Cohen, MD, Pediatric Neuro-Oncology, Departments of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland John Glod, MD, PhD, Department of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland Arnold C. Paulino, MD, Department of Radiation Oncology, Emory University, Atlanta, Georgia Radiation therapy has long been a mainstay in the treatment of ependymoma. Concerns about the long-term effects of radiation therapy have made many parents and caregivers wary of this treatment modality. However, with the advent of conformal radiation and evidence supporting its use in younger children (ie, < 3 years old), the standard of care for childhood ependymoma is rapidly evolving to include immediate postoperative radiation therapy for all pediatric patients. The role of chemotherapy in the treatment of ependymoma has diminished recently because (1) chemotherapy fails to

delay radiation therapy for a meaningful period of time; (2) tumors that progress during chemotherapy do not respond as well to subsequent irradiation; and (3) the combination of chemotherapy and irradiation does not improve overall survival. However, chemotherapy may make residual tumor more amenable to a second resection. Fewer than 50% of pediatric patients with ependymoma undergo complete resection before receiving radiation therapy. Because the extent of resection is one of the most important prognostic factors in the treatment of this disease, increasing the rate of complete resections is a significant means of increasing long-term survival. By incorporating current concepts of ependymoma, a more uniform approach to the treatment of this disease can be developed. In addition, by combining the best available means of detecting and managing side effects, the future for pediatric patients with ependymoma remains optimistic. This review presents historical and current practices used to treat ependymoma, and is intended to provide an information framework for caregivers so that they can assist parents in the decision-making process. [ONCOLOGY 16:629-648, 2002]

E pendymoma accounts for 8% to 10% of all childhood

central nervous system (CNS) tumors, with fewer than 170 new cases diagnosed annually in the United States in children and adults younger than 25 years old.[1] The mean age at the time of diagnosis ranges from 51 to 71 months,[2-5] and 25% to 40% of those diagnosed are younger than age 3.[6] Survival statistics for ependymoma are generally disappointing: The historical 5-year survival estimate is 50% to 64%, and the historical progression-free survival estimate is 23% to 45%.[2,4,7-9] Recurrences are typically local, and the median time to recurrence is 13 to 25 months.[2-4,7,9,10] Approximately 20% of failures involve distant recurrence, and late recurrences are not uncommon. Ependymoma develops from the neuroepithelial lining of the ventricles of the brain and the central canal of the spinal cord; 90% of tumors are located intracranially, with 30%

occurring above the tentorium and 60% below it (Figure 1).[1] Supratentorial ependymoma arises either from the lateral or third ventricle (60%) or from the cerebral hemisphere (40%).[1,11] Infratentorial ependymoma arises from one of three specific sites within the fourth ventricle: the floor (60%), the lateral aspect (30%), or the roof (10%).[12,13] Tumors that arise from the floor of the fourth ventricle may extend through the foramen of Magendie and over the dorsal surface of the spinal cord. Those that arise from the lateral aspect of the fourth ventricle can extend out of the foramen of Luschka and into the cerebellopontine angle and along the anterior aspect of the pons and medulla (Figure 2). Complete surgical removal of posterior fossa ependymoma arising from the floor or lateral aspect of the fourth ventricle is difficult because these tumors are typically close to the surface of the brainstem and cranial nerves. Fortunately, neuraxis dissemination at the time of diagnosis is rare and occurs in fewer than 7% of patients (Figure 3).[3]

Prognostic Factors

Numerous studies have sought to identify prognostic factors for intracranial ependymoma; most have been single-institution, retrospective reports that span several decades and consequently include numerous advances in neuroimaging, neurosurgery, radiation oncology, chemotherapy, and supportive measures. Surgical resection appears to be the most important prognostic factor.[2-5,7-11,14] In patients with completely resected tumors, the 5-year survival estimate is 67% to 80% and the 5-year progression-free survival estimate is 51% to 75%. Among patients with incompletely resected tumors, the 5-year survival estimate is 22% to 47%, and the 5-year progression-free survival estimate is 0% to 26% (Figure 4). Age at Diagnosis Age, at the time of diagnosis, may also be an important prognostic factor. Very young children typically have a poorer outcome.[4,7,15] For children younger than 3 years old at diagnosis, Pollack et al[7] reported a 5-year survival

estimate of 22% and a progression-free survival estimate of 12%. In older children, the 5-year survival estimate is 75%, and the progression-free survival estimate is 60%. Duffner et al[16] reported the experience of the Pediatric Oncology Group (POG) in very young children. For children who were younger than age 3 and had undergone gross total resection, they calculated a 5-year survival rate of 61%, whereas for those who had undergone subtotal resection, the estimate was 30%. The POG study also showed a 63% 5-year survival for young children (aged 24 to 35 months) in whom radiation therapy was delayed for 1 year, but a 26% 5-year survival for infants and very young children (aged 0 to 23 months) in whom radiation therapy was delayed for 2 years. The POG findings suggest that the poor survival estimates frequently reported for very young children are most likely related to the higher incidence of infratentorial tumors, the lower rate of complete resection, and the delay in the administration of radiation therapy. Historic studies have shown that patients with ependymoma who receive radiation therapy experience a better outcome than those who are not treated with irradiation.[17,18] In addition, one study suggested that the improvement in outcome may be radiation dose-dependent (ie, higher doses may improve outcome).[19] However, no randomized trials have unequivocally demonstrated that improved outcome is caused solely by radiation therapy; other factors such as extent of resection and age at the time of diagnosis also contribute to the outcome. Histologic Grade of the Tumor One of the most controversial prognostic factors in childhood ependymoma is the histologic grade of the tumor. Although numerous reports have suggested that patients with differentiated ependymoma achieve a better outcome than do those with anaplastic ependymoma,[11,17,20-25] some investigators believe that histologic grade has no prognostic significance. We recently reported histologic characterization of tumors and outcome in a contemporary series of 50 patients.[25] In

a blinded review of pathology, we determined that histologic grade was significantly related to progression-free survival after irradiation (P < .001). The 2-year event-free survival estimate (± SE) was 32% ± 14% for patients with anaplastic ependymoma and 84% ± 7% for patients with differentiated ependymoma. Statistical significance was maintained when the analysis was adjusted for age (< 3 years), chemotherapy with or without tumor progression before radiation therapy, and extent of resection. The finding of a poor progression-free survival estimate after irradiation for patients with anaplastic ependymoma parallels the findings from other contemporary series.[19,24] Data from the blinded pathology review at St. Jude[25] also showed that anaplastic ependymoma was more likely to occur in the supratentorial brain (P = .002). Of 12 patients with supratentorial tumor, 6 experienced a recurrence despite gross total resection and irradiation. Histologic evaluation plays an important role in the design and interpretation of prospective trials and in determining the significance of prognostic factors in the current treatment era (Figure 5). Cooperative multi-institutional protocols will enable us to determine the significance of the various factors that will be used to estimate prognosis and stratify individual treatments.

Treatment

The standard of care for ependymoma is maximal surgical resection with an acceptable neurologic outcome followed by postoperative radiation therapy directed at the site of the primary tumor. Immediate postoperative irradiation is not a widely accepted practice in the treatment of children younger than age 3; multiagent chemotherapy has typically been administered in an effort to delay or avoid irradiation. However, an obvious role for chemotherapy has not been demonstrated for patients with ependymoma, especially those older than age 3. The poor outcome of children younger than age 3 has been attributed in part to the delay in administering radiation therapy. Therefore, the approach for this very young group of patients with ependymoma should be

reevaluated in light of recent advances in radiation therapy. Surgery Ependymoma is a relatively slow-growing tumor with a propensity for local invasion. Subarachnoid dissemination is rare and considered incurable. Because the predominant pattern of failure for ependymoma is local, aggressive measures of local control are essential. Several institutional retrospective reviews[2-5,7,8,10,11] and two prospective phase III trials[9,16] have shown that the extent of surgical resection is the most consistent prognostic factor for patients with ependymoma. Sutton et al[5] retrospectively evaluated 45 patients with ependymoma and found that the 5-year survival estimate after total or near total resection was 60%; the 5-year survival estimate after subtotal resection (defined as < 90% tumor resection) was 21%. In a similar retrospective review of 40 patients, Pollack et al[7] found that 5-year survival after gross total resection was 80%; after partial resection (ie, less than gross total resection), it was 22%. Perilongo et al[3] retrospectively evaluated 92 children with ependymoma who participated in the Italian Pediatric Neuro-Oncology Group. For patients who had undergone gross total resection, the 10-year survival estimate was 70%, and the progression-free survival estimate was 57%; for patients who had undergone subtotal resection, the 10-year survival estimate was 32%, and the 10-year progression-free survival estimate was 11%. Finally, Robertson et al[9] prospectively treated 32 patients in the Children's Cancer Group (CCG) Protocol 921. They found that the 5-year progression-free survival was 66% for patients with residual tumor measuring 1.5 cm², and 11% for those with residual tumors measuring more than 1.5 cm². Resection Alone Successful treatment of newly diagnosed or recurrent intracranial ependymoma by resection alone has been reported by two independent groups.[26,27] Hukin et al[26] reported 10 pediatric cases in which gross total resection was

the only initial therapy for intracranial ependymoma (eight supratentorial tumors and two posterior fossa tumors). At a median follow-up of 48 months, seven patients were free of disease without further intervention, and three patients experienced tumor recurrence at 9, 10, and 20 months after resection. Two patients with recurrence were effectively treated with an additional surgical procedure and postoperative radiation therapy. Palma et al[27] reported on their success in treating supratentorial ependymoma with surgery alone. Of 12 surviving patients, 6 in their original series of 23 patients were treated with surgery alone, and only 1 experienced a recurrence after 10 years of follow-up. These findings indicate that some patients with intracranial ependymoma --probably those with supratentorial tumors--require resection only. Thus, radiation therapy and its potential for late effects might be delayed until the time of recurrence for a very select group of patients. Although complete resection is instrumental in the long-term, event-free, and overall survival of patients with childhood ependymoma, it is performed in only 42% to 62% of patients.[4,5,7,8] Complete resection is more easily accomplished for tumors in supratentorial locations and those originating from the roof of the fourth ventricle. Aggressive attempts to resect tumors in other locations, including those involving the lower cranial nerves, are associated with increased morbidity. Second Resection Despite the high rate of incomplete initial resections, few studies have included a second surgical procedure for patients with residual disease.[28,29] The timing of a second resection is the subject of debate: Some oncologists favor the use of chemotherapy between the initial and second resections. The purpose of administering chemotherapy before a second resection is to make the tumor more amenable to resection and to prevent tumor progression during the interval between procedures. Foreman et al[28] reported second resections in

five patients with residual tumors located in the fourth ventricle. One patient underwent an immediate second-look procedure, and the other four received short courses of chemotherapy before a second-look procedure. Gross total resection was achieved with the second procedure in four of the five patients. No severe morbidity was reported after the second resection; three of the patients remained progression-free at 23, 25, and 34 months after the second procedure and postoperative radiation therapy. From April 1997 through April 2000, 40 pediatric patients were referred to St. Jude Children's Research Hospital for treatment of intracranial ependymoma[30]; 24 patients (60%) underwent complete resection, and 16 (40%) had residual tumor after their initial procedure and prior to referral. Of those 16, 12 were considered candidates for additional resection based on the location of the residual tumor and neurologic status at the time of evaluation. A complete resection was performed in 10 patients and a near total resection in 2 patients with the second procedure. By combining the number of patients with a complete resection after their initial procedure with the number of those with complete resection after a second procedure, we increased the group's rate of complete resection to 85% (Figure 6). The operative morbidity of these patients was also determined. Significant morbidity, defined as lower cranial neuropathy necessitating gastrostomy or tracheostomy, occurred in 4 of the 24 patients with initial complete resections and 4 of the 16 patients with initial incomplete resections. Significant morbidity occurred in only one patient who underwent a second resection. Of the 12 patients who underwent a second resection, 6 had tumors that progressed during the interval between surgical procedures, despite administration of chemotherapy. It is generally agreed that a complete resection--ie, one that results in a very low probability of leaving even microscopic residual tumor--is rarely achieved in ependymoma. Complete resection may be possible for patients with supratentorial tumors when a margin of normal tissue

surrounding the tumor is also removed and biopsies of the operative cavity are negative. Biopsies of the operative cavity are seldom performed; however, such biopsies could be therapeutically beneficial and could contribute to the planning of radiation treatment. Resection Classification Current management of childhood ependymoma relies on three principal classifications of resection (Figure 7 and Table 1). A resection is classified as a gross total procedure when either no visible tumor or only microscopic tumor is identified with the operating microscope after resection, and no evidence of disease is identified in postoperative neuroimaging studies. Although the classification of near total resection has not been adequately defined, it generally includes patients with minimal residual tumor for whom a second resection would produce no benefit. For this reason, such patients are often treated in the same manner as those who have undergone gross total resection. In the current management of childhood ependymoma, a resection is classified as near total when minimal residual tumor is present. For purposes of future studies, this could be an area on a single image (< 1.5 cm²), a single greatest dimension on a single image (< 5 mm), or a volume (to be determined). A resection is classified as subtotal, or incomplete, when macroscopically visible tumor is identified with the operating microscope after resection, and residual tumor larger than that used to define near total resection is present on postoperative neuroimaging studies. Radiation Therapy For nearly 20 years, the avoidance of radiation therapy has been the hallmark of trial designs for the treatment of brain tumors in young children. Strategies that either delay or avoid irradiation have been justified on the basis of concerns about the effects of irradiation on neurologic, endocrine, and cognitive functions. Although irradiation-induced deficits have not been well documented in cases of childhood ependymoma, this therapy has, in the past, paralleled that used for other more common childhood tumors such as

medulloblastoma (the effects of which have been well documented). Since 1977, postoperative radiation therapy has been considered standard treatment for patients with ependymoma. Supportive Studies Mork et al[17] were the first to demonstrate that postoperative radiation therapy improves outcome in ependymoma patients. These investigators reported a survival estimate of 17% for patients who underwent resection alone vs a 40% survival estimate for those who underwent resection and postoperative irradiation. Radiation therapy has been routinely administered to patients with ependymoma who are 3 years of age or older, but, as yet, no studies have critically challenged its role in the postoperative treatment of patients in this age group. On the other hand, the role of radiation therapy has been evaluated in several studies in infants and children younger than age 3, including the POG 8633 study.[16] This study showed that young children with completely resected ependymoma in whom radiation therapy was delayed for 2 years experienced a significantly worse outcome (5-year survival estimate: 38%) than those in whom therapy was delayed for 1 year (5-year survival estimate: 88%). This finding supports the use of radiation therapy and contradicts the policy of delaying treatment for the time intervals specified in the study. Although a better event-free survival may be achieved in patients who have undergone complete resection, the volume of residual tumor in those undergoing incomplete resection may be smaller in this advanced neurosurgical era than it was in prior treatment eras. Indeed, more recent findings suggest that a contemporary incomplete resection differs considerably from one achieved with the technology available more than a decade ago.[25,30] Five-year progression-free survival estimates as low as 0% to 26% have been reported in patients with macroscopic residual tumor after surgery, despite the use of radiation therapy.[2,5,7,8,14] Of course, the neurosurgical era from which these findings were derived should be taken into

account. Optimal Radiation Dose and Volume The optimal dose of radiation remains unclear. The evaluation of a dose-response relationship for a given type of tumor requires prospective evaluation. Retrospectively, an increase in the dose of radiation administered to the primary site appears to improve local control.[18,19] The recent POG 9132 study used hyperfractionated radiation therapy delivered to the primary site at a total dose of 6,960 cGy for the treatment of posterior fossa ependymoma. The investigators found that 19 patients who underwent subtotal resection had a better outcome (4-year event-free survival: 50%) than did a comparable group of patients who participated in the earlier POG 8532 study, which used a lower total dose of conventional radiation (4-year event-free survival: 24%).[31] Hyperfractionated radiation therapy did not improve survival estimates in patients with completely resected tumors. In addition, several retrospective studies have failed to demonstrate any benefits associated with the use of prophylactic craniospinal irradiation.[4,13,19,32] Conformal radiation therapy limits the highest doses to the primary site and decreases the dose received by normal tissues. Reducing the dose received by normal tissues is logical in children, but requires systematic definition of the treatment volume and prospective study to determine that irradiation using more limited volumes does not increase the risk of marginal treatment failures. We recently reported the preliminary results of a St. Jude protocol (RT-1) in which 64 pediatric patients with localized ependymoma received treatment between July 1997 and October 2000. An anatomically defined, clinical target volume margin of 10 mm surrounding the postoperative residual tumor and tumor bed was used. Only six failures occurred after a median follow-up of 17 months (range: 3 to 43 months) in the group of patients with a median age of 2.9 years (range: 1.1 to 21 years). With the exception of one patient who developed metastatic disease with no evidence of local failure, failures at the primary site were encompassed

by the prescription isodose. Most patients received a total radiation dose of 59.4 Gy. These preliminary results demonstrate that the volume of irradiation can be substantially reduced without compromising disease control in pediatric patients with ependymoma.[33] Evaluating Outcome Reducing the volume of irradiation will only be beneficial if the rate of disease control remains the same and the incidence of side effects decreases. Several reports have compared outcomes in terms of disease control, but few investigations of functional outcome have been unbiased regarding radiation therapy. Pediatric patients have never been systematically evaluated for side effects before undergoing radiation therapy; thus, the side effects reported for these studies include those caused by the tumor, resection, radiation therapy, and possibly other therapies including chemotherapy. A trial that compares conventional radiation therapy with conformal radiation therapy will never be performed because the dosimetric advantages of the newer treatment are obvious. Investigations that include careful evaluations performed before and after irradiation will be necessary to understand the effects of radiation dose and volume on functional outcome in pediatric patients (Figure 8). At St. Jude, patients with localized primary brain tumors such as ependymoma that require only focal irradiation are serially evaluated for evidence of CNS effects before and after radiation therapy. Before irradiation, morbidity in this group is high; nearly 50% of those with posterior fossa tumors show evidence of endocrinopathy, as determined by dynamic tests of endocrine function.[34] The most common endocrinopathies include growth hormone deficiency, thyroid hormone deficiency, and adrenal insufficiency. Preirradiation morbidity has also been assessed by cognitive and neurologic measures in this patient population. Low-average IQ (90 ± 17)[35] and higher hearing thresholds (~20 to 25 dB HL) have been observed for children with ependymoma prospectively evaluated prior to radiation therapy.

During the development of conformal treatment plans, normal tissue structures should be contoured and the dose determined for that volume. These measures will provide valuable information that can be used to examine the effects of radiation dose and volume on the function of healthy tissue. For example, the integral dose and volume for the temporal lobe may be correlated with neuropsychometric measures, whereas the integral dose and volume for the hypothalamus may be correlated with evidence of endocrinopathy (Figure 9). Assessing the effects of radiation dose and volume requires baseline and serial evaluation after irradiation, evidence of effect and observation for a period of time during which the effect is likely to be observed.[36] Using integrated three-dimensional dosimetry, we recently demonstrated the effects of low and high-dose hypothalamic irradiation on the time course of growth hormone deficiency up to 12 months after irradiation.[37] Such information may be used a priori to optimize treatment planning and predict outcome. In assessing cognitive outcomes after conformal radiation therapy, we have not observed a decline in IQ estimates during the first 30 months after treatment; this finding holds for the youngest children (age < 6 years) with infratentorial tumors treated to 59.4 Gy.[35] The need for additional follow-up notwithstanding, this group is faring markedly better than comparably aged patients treated for medulloblastoma.[38,39] Recurrence after conformal radiation therapy should also be evaluated in terms of dose and volume received. By comparing these measures with neuroimaging studies performed at the time of failure, we can determine the pattern of failure (Figure 10). Chemotherapy Several retrospective reviews have assessed the effectiveness of chemotherapy in the treatment of newly diagnosed ependymoma, and none have found that it improves overall survival.[2-5,7,19,40] The CCG 942 study is the only randomized trial that compared survival after irradiation alone with survival after irradiation and chemotherapy in

pediatric patients (aged 2 to 16 years) with ependymoma. The investigators concluded that adjuvant chemotherapy with lomustine (CeeNu), vincristine, and prednisone did not improve outcome.[6] The CCG 921 study, a prospective randomized study of radiation therapy followed by either lomustine, vincristine, and prednisone or a combination of agents known as "8 in 1" (ie, eight drugs in 1 day), used survival analyses to demonstrate that the outcome of patients who received chemotherapy was no better than that of historical controls.[9] Adjuvant Combination Chemotherapy Ependymoma does respond to some chemotherapeutic regimens. However, the findings of single-agent phase II studies of recurrent ependymoma have been disappointing. Cisplatin has produced one of the highest response rates (30%) of all agents used to treat recurrent ependymoma.[41] Recent reports of adjuvant combination chemotherapy in pediatric patients with newly diagnosed ependymoma have demonstrated encouraging responses without improving survival, suggesting a limited role. For example, White et al[42] reported an 86% response rate to four cycles of vincristine, etoposide, and cyclophosphamide (Cytoxan, Neosar) in seven children younger than age 4 who had been newly diagnosed. Duffner et al[43] achieved a 48% response rate with two cycles of vincristine and cyclophosphamide administered to 25 infants and children younger than age 3. Mason et al[44] reported a 16% response rate to four or five cycles of cisplatin, vincristine, etoposide, and cyclophosphamide in 10 children younger than age 6. Fouladi et al[45] demonstrated a 33% response rate with two cycles of ifosfamide (Ifex), etoposide, and carboplatin (Paraplatin) in six children with newly diagnosed ependymoma. A recent prospective study by Needle et al[10] used irradiation followed by carboplatin and vincristine alternating with ifosfamide and etoposide in patients older than 36 months with newly diagnosed ependymoma. The 5-year progression-free survival estimates of the 10 patients with incompletely resected tumors was 80%. These excellent

survival statistics for patients with incompletely resected ependymoma suggested that chemotherapy may be beneficial. However, it cannot be determined if their favorable outcome was related to the volume of residual tumor, radiation therapy, or histology. Unfortunately, radiation therapy was not standardized in this study; the fact that a portion of the patients received hyperfractionated radiation therapy confounds the analysis of the results. Standard vs Dose-Intensive Chemotherapy The POG 9233 study compared standard chemotherapy (six 12-week cycles of cisplatin, cyclophosphamide, etoposide, and vincristine) and dose-intensive chemotherapy (eight 9-week cycles of the same agents with differences in relative intensity) in a group of infants with brain tumors including ependymoma. Event-free survival estimates were significantly increased for patients with ependymoma treated with dose-intensive chemotherapy, yet there was no difference in overall survival estimates. The relative dose intensities (compared with standard doses) were 1.67 for cisplatin, 2.67 for cyclophosphamide, 1.54 for etoposide, and 1.33 for vincristine.[46] Grill et al[47] recently reported the results of a French Society of Pediatric Oncology trial in 73 children treated with multiagent chemotherapy for 16 to 18 months after maximal resection. Irradiation was not included in the treatment regimen. Progression-free survival estimates at 2 and 4 years were 33% and 22%, respectively, with 50% of patients relapsing during the planned chemotherapy course. Salvage therapy included additional surgery, radiation therapy, and for some, high-dose chemotherapy. Overall survival for the entire group was approximately 52% at 5 years and for the patients who relapsed, 49% at 2 years after relapse. As expected, supratentorial tumors and children with complete resection fared better; 23% were alive at 4 years without irradiation. Chemotherapy and Second Resection Chemotherapy may make residual tumors more amenable to complete surgical resection. Foreman et al[28] used

chemotherapy between the initial and second resections in four patients with ependymoma. After chemotherapy, all the patients had viable tumor; complete resections were performed in three of the four, all of whom remained progression-free at 23 to 34 months after second-look surgery. The subjective impression of the investigators was that the tumors were better defined and easier to dissect after chemotherapy. Platinum-based therapy has produced the best results in studies with limited numbers of patients. Response rates as high as 67% were reported in a recent review by Gornet.[48] Carboplatin and etoposide are frequently used because they can penetrate the CNS. Results suggest that some neoplasms, particularly slower-growing tumors, respond better with prolonged exposure to chemotherapeutic agents. Needle et al[49] demonstrated the effectiveness of treatment with oral etoposide in five patients with ependymoma; two patients responded, including one who achieved a complete response (Figure 11). Future Role of Chemotherapy Chemotherapy may serve four important functions in the future: Such treatment may be used (1) to bridge the interval necessary while planning a second resection; (2) to make the tumor more amenable to resection and improve the rate of complete resection at the time of the second procedure; (3) to reduce the morbidity of the second resection; and (4) bridge the interval required to prepare a child who has suffered neurologic complications from tumor or surgery for daily radiation therapy and often anesthesia. The selection of the best agents, the schedule of delivery, and the duration of chemotherapy necessary to achieve these goals are difficult to determine given the range of responses, the differences in toxicity profiles, and the lack of data from which to model such a study. Most investigators prefer to use combinations of drugs including carboplatin or cisplatin, etoposide, cyclophosphamide, and vincristine. Concerns about the use of carboplatin, which has a better toxicity profile, persist among investigators because this agent's equivalency to cisplatin has not been demonstrated.

The findings of Gaynon et al[50] support the use of carboplatin for patients with ependymoma. These researchers found a 40% overall response rate for patients with ependymoma who had not been previously treated with cisplatin. One of the principal reasons for using carboplatin is to avoid ototoxicity. Although one or two courses of cisplatin may be relatively less ototoxic than a longer or more conventional course of the agent, the risk of substantial and permanent hearing loss increases linearly with each dose.[51] In addition, substantial concerns about hearing loss arise for patients who receive cisplatin and radiation therapy.

Rationale for Future Studies

A national treatment standard for all pediatric patients with intracranial ependymoma is needed. Opinions about what that standard should be are varied, despite an apparent consensus among the members of cooperative groups that a national study using a conformal radiation therapy regimen similar to that tested at St. Jude should be initiated. Ependymoma is a rare tumor and, with few exceptions, is rarely seen by pediatric oncologists. Therefore, only multi-institution studies conducted by a cooperative group such as the Children's Oncology Group can lead to improvements in outcome for children with ependymoma. Local control is the primary treatment objective because local recurrence is the predominant mode of failure. The local failure rate is highest among patients who have undergone incomplete resection (despite postoperative radiation therapy), and contemporary chemotherapy does not improve overall survival. However, marked advances have been made in neurosurgical technique and radiation technology. These advances should significantly improve the outcome of patients with childhood ependymoma by increasing the rate of complete resection without added morbidity and by reducing or eliminating side effects attributable to radiation therapy. In addition, potentially important prognostic variables such as age, histologic characteristics, and location of primary tumor need to be evaluated in the context of a contemporary clinical trial.

The availability of neurosurgeons and radiation oncologists with the expertise to treat pediatric ependymoma patients varies among institutions. Through the design and implementation of a multicenter treatment trial, we could increase the rate of complete resection and systematically deliver radiation therapy that is safe and effective. We could also develop a standard approach to assist caregivers who are less familiar with the treatment of this rare disease. The proposed schema of the next Children's Oncology Group study to further investigate the current management of childhood ependymoma in a multi-institutional cooperative trial is diagrammed in Figure 12. We plan to administer a 7-week course of chemotherapy that consists of carboplatin, cyclophosphamide, etoposide, and vincristine to patients who have undergone incomplete resection before a second surgical procedure is performed. The trial will also include conformal radiation therapy for all patients with ependymoma (maximal dose: 59.4 Gy; clinical target volume: 1.0 cm), and an observational study of pediatric patients who have undergone complete resection of supratentorial, differentiated ependymoma. Observation has not been suggested for supratentorial anaplastic tumors based on the St. Jude data.[25]

Current Recommendations

Immediate postoperative conformal radiation therapy is recommended for the treatment of childhood ependymoma on the basis of the following criteria: Maximal resection of the primary tumor, including second resection to achieve gross total resection Diagnosis of ependymoma confirmed by an experienced neuropathologist No evidence of tumor dissemination beyond the primary site as determined by neuroimaging studies of the brain and spine and by cytologic examination of cerebrospinal fluid (CSF) obtained from the lumbar CSF space Patient older than 12 months at the time of irradiation Presence of an experienced radiation oncologist who

specializes in the treatment of brain tumors in pediatric patients and a radiation therapy department equipped to administer conformal radiation therapy to children who require general anesthesia.

References

1. Ries LAG et al: Cancer Statistics Review, 1973-1997. National Cancer Institute, Bethesda, Md, 2000. 2. Foreman NK, Love S, Thorne R: Intracranial ependymomas: Analysis of prognostic factors in a population-based series. Pediatr Neurosurg 24:119-125, 1996. 3. Perilongo G, Massimino M, Sotti G, et al: Analyses of prognostic factors in a retrospective review of 92 children with ependymoma: Italian Pediatric Neuro-oncology Group. Med Pediatr Oncol 29:79-85, 1997. 4. Horn B, Heideman R, Geyer R, et al: A multi-institutional retrospective study of intracranial ependymoma in children: Identification of risk factors. J Pediatr Hematol Oncol 21:203-211, 1999. 5. Sutton LN, Goldwein J, Perilongo G, et al: Prognostic factors in childhood ependymomas. Pediatr Neurosurg 16:57-65, 1990-1991. 6. Evans AE, Anderson JR, Lefkowitz-Boudreaux IB, et al: Adjuvant chemotherapy of childhood posterior fossa ependymomas: Craniospinal irradiation with or without adjuvant CCNU, vincristine, and presdnisone: A Children's Cancer Group study. Med Pediatr Oncol 27:8-14, 1996. 7. Pollack IF, Gerszten PC, Martinez AJ, et al: Intracranial ependymomas of childhood: Long-term outcome and prognostic factors. Neurosurg 37:655-666, 1995. 8. Rousseau P, Habrand J, Sarrazin D, et al: Treatment of intracranial ependymomas of children: Review of a 15-year experience. Int J Radiat Biol Phys 28:381-386, 1994.

9. Robertson PL, Zeltzer PM, Boyett JM, et al: Survival and prognostic factors following radiation therapy and chemotherapy for ependymomas in children: A report of the Children's Cancer Group. J Neurosurg 88:695-703, 1998. 10. Needle MN, Goldwein JW, Grass J, et al: Adjuvant chemotherapy for the treatment of intracranial ependymoma of childhood. Cancer 80:341-347, 1997. 11. Nazar GB, Hoffman HJ, Becker LE, et al: Infratentorial ependymomas in childhood: Prognostic factors and treatment. J Neurosurg 72:408-417, 1990. 12. Ikezaki K, Matsushima T, Inoue T, et al: Correlation of microanatomical localization with postoperative survival in posterior fossa ependymomas. Neurosurgery 32:38-44, 1993. 13. Sanford RA, Gajjar A: Ependymomas. Clin Neurosurg 44:559-570, 1997. 14. Healey EA, Barnes PD, Kupsky WJ, et al: The prognostic significance of postoperative residual tumor in ependymoma. Neurosurgery 28:666-671, 1991. 15. Sala F, Talacchi A, Mazza C, et al: Prognostic factors in childhood intracranial ependymomas. Pediatr Neurosurg 28:135-142, 1998. 16. Duffner PK, Krischer JP, Sanford RA, et al: Prognostic factors in infants and very young children with intracranial ependymomas. Pediatr Neurosurg 28:215-222, 1998. 17. Mork SJ, Loken AC: Ependymoma: A follow-up study of 101 cases. Cancer 40:907-915, 1977. 18. Shuman RM, Alvord EC, Leech RW: The biology of childhood ependymomas. Arch Neurol 32:731-739, 1975. 19. Merchant TE, Haida T, Wang MH, et al: Anaplastic ependymoma: Treatment of pediatric patients with or without craniospinal radiation therapy. J Neurosurg 86:943-949, 1997. 20. Pierre-Kahn A, Hirsch JF, Roux FX, et al: Intracranial

ependymomas in childhood. Survival and functional results of 47 cases. Childs Brain 10:145-156, 1983. 21. Shaw EG, Evans RG, Scheithauer BW, et al: Postoperative radiotherapy of intracranial ependymoma in pediatric and adult patients. Int J Radiat Oncol Biol Phys 13:1457-1462, 1987. 22. Kovnar E, Kun L, Burger P, et al: Patterns of dissemination and recurrence in childhood ependymoma: Preliminary results of Pediatric Oncology Group Protocol #8532. Ann Neurol 30:457, 1991. 23. Kovalic JJ, Flaris N, Grigsby PW, et al: Intracranial ependymoma long-term outcome, patterns of failure. J Neurooncol 15:125-131, 1993. 24. Timmermann B, Kortmann RD, Kuhl J, et al: Combined postoperative irradiation and chemotherapy for anaplastic ependymoma in childhood: Results of the German Prospective Trials Hit '88/'89 and Hit '91 (abstract 122). Int J Radiat Oncol Biol Phys 42(suppl 1):185, 1998. 25. Merchant TE, Jenkins JJ, Burger PC, et al: The influence of histology on the time to progression after irradiation for localized ependymoma in children. Int J Radiat Oncol Biol Phys. In press. 26. Hukin J, Epstein F, Lefton D, et al: Treatment of intracranial ependymoma by surgery alone. Pediatr Neurosurg 29:40-45, 1998. 27. Palma L, Celli P, Mariottini A, et al: The importance of surgery in supratentorial ependymomas. Long-term survival in a series of 23 cases. Childs Nerv Syst 16:170-175, 2000. 28. Foreman NK, Love S, Gill SS, et al: Second-look surgery for incompletely resected fourth ventricle ependymomas: Technical case report. Neurosurgery 40:856-860, 1997. 29. Sanford RA, Kun LE, Heideman RL, et al: Cerebellar pontine angle ependymoma in infants. Pediatr Neurosurg 27:84-91, 1997.

30. Osterdock RJ, Sanford RA, Merchant TE: Pediatric ependymoma (40 in 36 months). Paper presented at the annual meeting of American Association of Neurosurgeons (AANS)/Central Nervous System (CNS) Section on Pediatric Neurological Surgery; December 6-9, 2000; Coronado, California. 31. Kovnar E, Curran W, Tomita, et al: Hyperfractionated irradiation for childhood ependymoma: Improved local control in subtotally resected tumors (abstract). Childs Nerv Syst 14:489, 1998. 32. Vanuytsel LJ, Bessell EM, Ashley SE, et al: Intracranial ependymoma: Long-term results of a policy of surgery and radiotherapy. Int J Radiat Oncol Biol Phys 23:313-319, 1992. 33. Merchant TE, Zhu Y, Thompson SJ, et al: Preliminary results from a phase II trial of conformal radiation therapy for localized pediatric brain tumors. Int J Radiol Oncol Biol Phys 52:325-332, 2002. 34. Merchant TE, Smith JM, Williams T, et al: Pre-irradiation endocrinopathies in pediatric patients determined by dynamic tests of endocrine function. Paper presented at the 6th International Conference on the Long-Term Complications of Treatment of Children and Adolescents for Cancer; June 23-24, 2000; Niagara-on-the-Lake, Ontario, Canada. 35. Merchant TE, Goloubeva O, Kiehna EN, et al: Neurocognitive effects of radiation therapy. 43rd Annual Meeting of the American Society of Therapeutic Radiology and Oncology. San Francisco, Nov 4-8, 2001. 36. Merchant TE, Smith JM, Williams T, et al: Pre-irradiation endocrinopathies in pediatric patients determined by dynamic tests of endocrine function. Sixth International Conference on the Long-Term Complications of Treatment of Children and Adolescents for Cancer. Niagara-on-the-Lake, Ontario, Canada, June 23-24, 2000. 37. Merchant TE, Goloubeva O, Pritchard DL, et al: Radiation dose-volume effects on growthy hormone

secretion. Int J Radiat Oncol Biol Phys 52:1264-1270, 2002. 38. Ris MD, Packer R, Goldwein J, et al: Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: A Children's Cancer Group study. J Clin Oncol 19(15):3470-3476, 2001. 39. Walter AW, Mulhern RK, Gajjar A, et al: Survival and neurodevelopmental outcome of young children with medulloblastoma at St. Jude Children's Research Hospital. J Clin Oncol 17(12):3720-3728, 1999. 40. Chiu JK, Woo SY, Ater J, et al: Intracranial ependymoma in children: Analysis of prognostic factors. J Neurooncol 13:283-290, 1992. 41. Bouffet E, Perilongo G, Canete A, et al: Intracranial ependymomas in children: A critical review of prognostic factors and a plea for cooperation. Med Pediatr Oncol 30:319-331, 1998. 42. White L, Kellie S, Gray E, et al: Postoperative chemotherapy in children less than 4 years of age with malignant brain tumors: Promising initial response to a VETOPEC-based regimen. A study of the Australian and New Zealand Children's Cancer Study Group (ANZCCSG). J Pediatr Hematol Oncol 20:125-130, 1998. 43. Duffner PK, Horowitz ME, Krischer JP, et al: Postoperative chemotherapy and delayed radiation in children less than 3 years of age with malignant brain tumors. N Engl J Med 328:1725-1731, 1993. 44. Mason WP, Grovas A, Halpern S, et al: Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. J Clin Oncol 16:210-221, 1998. 45. Fouladi M, Baruchel S, Chan H, et al: Use of adjuvant ICE chemotherapy in the treatment of anaplastic ependymomas. Childs Nerv Syst 14:590-595, 1998. 46. Strother D, Kepner J, Aronin PA, et al: Dose-intensive

chemotherapy prolongs event-free survival for very young children with ependymoma. Results of pediatric oncology group study 9233 (abstract 2302). Proc Am Soc Clin Oncol 19:585a, 2000. 47. Grill J, Le Delay MC, Gambarelli D, et al: Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: A multicenter trial of the French Society of Pediatric Oncology. J Clin Oncol 19:1288-1296, 2001. 48. Gornet MK, Buckner JC, Marks RS, et al: Chemotherapy for advanced CNS ependymoma. J Neurooncol 45:61-67, 1999. 49. Needle MN, Molloy PT, Geyer JR, et al: Phase II study of daily oral etoposide in children with recurrent brain tumors and other solid tumors. Med Pediatr Oncol 29:28-32, 1997. 50. Gaynon PS, Ettinger LJ, Baum ES, et al: Carboplatin in childhood brain tumors: A Children's Cancer Study Group Phase II trial. Cancer 66:2465-2469, 1990. 51. Cohen BH, Zweidler P, Goldwein JW, et al: Ototoxic effect of cisplatin in children with brain tumors. Pediatr Neurosurg 16:292-296, 1990-1991.

The Merchant Article Reviewed

Kenneth J. Cohen, MD Director, Pediatric Neuro-Oncology, Assistant Professor of Oncology and Pediatrics John Glod, MD, PhD Postdoctoral Fellow, Department of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland

E pendymoma is a rare central nervous system (CNS) tumor

in children, and our progress in treating this disease has been hampered by its rarity as well as by a nonuniform approach

to treatment among practitioners. Dr. Merchant's comprehensive review provides a framework for plotting a course of further progress in treating children with ependymoma. Optimal Local Control As the author points out, optimal local control has been repeatedly shown to be the single most important prognostic factor in the treatment of this disease, and achieving this goal begins with maximal surgical resection. Failure to perform a gross total or near total resection substantially decreases the likelihood of long-term disease control. To that end, one goal of the next Children's Oncology Group trial is emphasis on increasing the number of patients whose tumors are gross totally or near totally resected. Second surgery is recommended for patients who undergo an initial subtotal resection. In an attempt to facilitate the second surgery, chemotherapy is administered between the first and second resections in the hopes of rendering the tumor more amenable to complete removal and, perhaps, reducing the likelihood of disease dissemination in the interim. Following surgery, postoperative conformal radiation therapy is administered to all patients, with the exception of those with supratentorial, differentiated ependymomas whose tumors have been completely resected. Notably, and in contrast to other contemporary trials, children will receive irradiation if they are 1 year of age or older at the time of planned irradiation. Merchant argues, based on his own institutional experience, that in light of newer radiation techniques, irradiation in young children will likely result in fewer long-term neurologic sequelae than have been seen in the past, while improving long-term survival. To date, disease control in his series has been excellent, but the follow-up period is still relatively short. Long-Term Neurologic Outcome Aggressive attempts at local control appear to be a reasonable strategy to improve the treatment of patients with ependymoma. However, we must be careful to follow-up on

the possible consequences of this approach. Although there is reason to hope that the use of more modern radiation technology and neurosurgical techniques will improve the long-term neurologic outcome of survivors, this is by no means assured. Surgical procedures need to be performed by practitioners specifically skilled in pediatric neurosurgery. As Merchant points out, a variety of abnormalities (eg, neuroendocrine, cranial nerve dysfunction requiring G-tubes, or tracheostomies) manifest prior to the implementation of irradiation, suggesting a major impact of the primary tumor and the subsequent surgical intervention on outcome in these patients. The neurocognitive sequelae in patients receiving radiation therapy, particularly those under age 3, are still a major concern. Recent studies have shown that exposure to as low as 20 Gy can cause white matter changes evident on magnetic resonance imaging.[1] It is also clear that the posterior fossa, a frequent location of ependymoma in the pediatric population, is vulnerable to injury. In addition to its traditional role in motor processes, a growing body of evidence shows that the cerebellum plays a critical role in many cognitive functions.[2] A cerebellar cognitive affective syndrome has been described in adults[3] and children with damage to the cerebellum from tumor growth and surgery. These patients exhibit long-term sequelae such as behavioral problems and deficits in language processing and spatial memory,[4,5] as well as the frequently described phenomenon of postsurgical mutism. These findings suggest that injury to the cerebellum might be anticipated to have wide-ranging neurodevelopmental effects. It is imperative, therefore, that long-term neuropsychological outcome be monitored in patients, particularly the very young, who receive upfront irradiation following definitive surgery. This follow-up is particularly critical because if it is determined that the youngest children (eg, less than 2 years old) are disproportionately affected by irradiation, then perhaps an interval of delay might be recommended in future treatment trials. Study findings suggest that irradiation might be safely postponed for a period not to exceed 1 year.[6]

Conclusions Dr. Merchant has nicely summarized the chemotherapeutic literature related to ependymoma. The role of chemotherapy is evolving, with several agents demonstrating activity in this tumor, albeit with unclear evidence of the impact on event-free survival. Additional approaches are certainly needed, particularly for patients with distant spread of tumor, which is uniformly lethal. The author does not discuss the role of molecular diagnostics in the treatment of this tumor. There is a growing body of literature regarding the genetic abnormalities seen in these tumors. Ideally, the evolution of this knowledge might allow for more molecularly rational approaches to treatment, such as those that are being evaluated for other pediatric CNS tumors, most notably medulloblastoma. References 1. Steen RG, Koury BSM, Granja CI, et al: Effect of ionizing radiation on the human brain: White matter and gray matter T1 in pediatric brain tumor patients treated with conformal radiation therapy. Int J Radiat Oncol Biol Phys 49:79-91, 2001. 2. Fiez JA: Cerebellar contributions to cognition. Neuron 16:13-15, 1996. 3. Schmahmann JD, Sherman JC: The cerebellar cognitive affective syndrome. Brain 121:561-579, 1998. 4. Levisohn L, Cronin-Golomb A, Schmahmann JD: Neuropsychological consequences of cerebellar tumour resection in children: Cerebellar cognitive affective syndrome in a paediatric population. Brain 123:1041-1050, 2000. 5. Riva D, Giorgi C: The cerebellum contributes to higher functions during development: Evidence from a series of children surgically treated for posterior fossa tumours. Brain 123:1051-1061, 2000. 6. Duffner PK, Krischer JP, Sanford RA, et al: Prognostic

factors in infants and very young children with intracranial ependymomas. Pediatr Neurosurg 28:215-222, 1998.

The Merchant Article Reviewed

Arnold C. Paulino, MD Associate Professor, Departments of Radiation Oncology, Emory University, Atlanta, Georgia

Dr. Merchant provides a comprehensive overview of

intracranial ependymoma in children. As he points out, most of the current information regarding childhood intracranial ependymoma has come from single-institution retrospective reviews. Of the prognostic indicators mentioned in the article, both young age and subtotal resection are widely accepted. Children less than 3 years old have a worse prognosis than older children, possibly because of more aggressive tumor biology, reluctance to give postoperative radiotherapy, or use of lower doses of radiotherapy. Regarding the degree of surgical resection, assessment by postoperative imaging is more important than the neurosurgeon's perspective on whether a gross total or subtotal resection has been performed.[1,2] Tumor grade is a controversial prognostic factor. Our experience and that of others indicate a worse outcome for high-grade or anaplastic ependymomas[3,4]; however, cooperative group studies and other single-institution reviews have not verified this finding.[2,5] One problem concerning tumor grade is the lack of agreement among individual pathologists. In a study from the Children's Cancer Group, 22 (69%) of 32 cases had a discrepancy in the diagnosis on central review.[2] Radiotherapy Volume Perhaps one of the more controversial topics in ependymoma until recently has been the volume of irradiation. Studies from the 1970s to early 1980s reported a better outcome among patients receiving wide-field irradiation (craniospinal and whole-brain radiotherapy).[6] With the advent of better

imaging and surgical techniques, current evidence indicates that the predominant pattern of failure is local, regardless of tumor grade or location.[2-3,5] For infratentorial ependymomas, the entire posterior fossa does not need to be treated.[7] Our current recommendation for a nondisseminated ependymoma is local radiotherapy. Craniospinal irradiation has more toxicity and may protract treatment duration, which can affect eventual outcome.[8,9] Craniospinal radiotherapy is reserved for the less than 10% of children with neuraxis dissemination. Radiotherapy Dose Studies that have shown a dose response level for ependymoma indicate a dose threshold of 45 to 50 Gy.[10,11] More recent studies suggest that dose escalation in subtotally resected tumors may be beneficial. As Dr. Merchant correctly points out, the Pediatric Oncology Group (POG) study 9132 used hyperfractionated radiotherapy to a total dose of 69.6 Gy (1.2 Gy twice daily). The 4-year event-free survival rate was 50%, compared to 24% in an earlier POG study that used a lower total dose of conventional radiotherapy.[12] A study from the Children's Hospital of Philadelphia showed a 74% 5-year progression-free survival rate for a group of children who had received adjuvant chemotherapy.[13] Of the 19 children, 10 had undergone subtotal resection and 16 had received hyperfractionated radiotherapy to a dose ranging from 65 to 72 Gy. It is unclear whether the higher doses of radiotherapy or the use of chemotherapy was responsible for the better outcome. No Adjuvant Treatment Although no randomized study has been conducted, based on retrospective studies, the standard adjuvant treatment after surgical resection for ependymoma is postoperative radiotherapy. Recently, Hukin and colleagues challenged this dogma with a study in which 7 of 10 children (mostly with supratentorial ependymomas) treated with imaging-verified

gross total resection received no further therapy and did not relapse. Of the three children who relapsed, two were salvaged with reresection and radiotherapy.[14] Our experience showed that of five patients with infratentorial tumors who had imaging-verified gross total resection and did not receive any further treatment, four were locally controlled at 36 to 127 months after surgery.[7] In addition, Palma and colleagues reported long-term survival of four patients with supratentorial ependymomas treated with surgery alone.[15] The above findings indicate that there may be a subset of patients who do not require adjuvant treatment. A proposed future study of the newly formed Children's Oncology Group will look at surgery alone for low-grade, supratentorial tumors that have been completely resected. Chemotherapy I agree with Dr. Merchant regarding the role of chemotherapy. The only randomized trial that used adjuvant radiotherapy, with or without chemotherapy, did not show a benefit for chemotherapy.[16] The Children's Hospital of Philadelphia study used chemotherapy and higher doses of radiotherapy, but these results are difficult to interpret.[13] One recent study reported that giving chemotherapy to younger children resulted in the avoidance of radiotherapy in 40% and 23% of children at 2 and 4 years after the initiation of systemic treatment.[17] The real question is whether these same patients needed adjuvant therapy at all, since most of them had supratentorial tumors that had been completely resected. References 1. Healey EA, Barnes PD, Kupsky, et al: The prognostic significance of postoperative residual tumor in ependymoma. Neurosurgery 28:666-672, 1991. 2. Robertson PL, Zeltzer PM, Boyett JM, et al: Survival and prognostic factors following radiation therapy and

chemotherapy for ependymomas in children: A report of the Children's Cancer Group. J Neurosurg 88:695-703, 1998. 3. Paulino AC, Wen BC, Hussey DH, et al: Intracranial ependymomas: An analysis of prognostic factors and patterns of failure (abstract). Cancer J Sci Am 6:104-105, 2000. 4. Perilongo G, Massimino M, Sotti G, et al: Analyses of prognostic factors in a retrospective review of 92 children with ependymoma: Italian Pediatric Neuro-Oncology Group. Med Pediatr Oncol 29:79-85, 1997. 5. Rousseau P, Habrand JL, Sarrazin D, et al: Treatment of intracranial ependymomas of children: Review of a 15-year experience. Int J Radiat Oncol Biol Phys 28:381-386, 1993. 6. Salazar OM, Castro-Vita H, VanHoutte P, et al: Improved survival in cases of intracranial ependymoma after radiation therapy. Late report and recommendations. J Neurosurg 59:652-659, 1983. 7. Paulino AC: The local field in infratentorial ependymoma: Does the entire posterior fossa need to be treated? Int J Radiat Oncol Biol Phys 49:757-761, 2001. 8. Merchant TE, Haida T, Wang MH, et al: Anaplastic ependymoma: Treatment of pediatric patients with or without craniospinal radiation therapy. J Neurosurg 86:943-949, 1997. 9. Paulino AC, Wen BC: The significance of radiotherapy treatment duration in intracranial ependymoma. Int J Radiat Oncol Biol Phys 47:585-589, 2000. 10. Goldwein JW, Leahy JM, Packer RJ, et al: Intracranial ependymomas in children. Int J Radiat Oncol Biol Phys 19:1497-1502, 1990. 11. Chiu JK, Woo SY, Ater J, et al: Intracranial ependymoma in children: Analysis of prognostic factors. J Neurooncol 13:283-290, 1992. 12. Kovnar E, Curran W, Tomita T, et al: Hyperfractionated

irradiation for childhood ependymoma: Improved local control in subtotally resected tumors (abstract). Childs Nerv Syst 14:569, 1998. 13. Needle MN, Goldwein JW, Grass J, et al: Adjuvant chemotherapy for the treatment of intracranial ependymoma of childhood. Cancer 80:341-347, 1997. 14. Hukin J, Epstein F, Lefton D, et al: Treatment of intracranial ependymoma by surgery alone. Pediatr Neurosurg 29:40-45, 1998. 15. Palma L, Celli P, Cantore G: Supratentorial ependymomas of the first two decades of life: Long-term follow-up of 20 cases (including subependymomas). Neurosurgery 32:169-175, 1993. 16. Evans AE, Anderson JR, Lefkowitz-Boudreaux IB, et al: Adjuvant chemotherapy of childhood posterior fossa ependymoma: Craniospinal irradiation with or without adjuvant CCNU, vincristine, and prednisone. Med Pediatr Oncol 27:8-14, 1996. 17. Grill J, Deley ML, Gambarelli D, et al: Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: A multicenter trial of the French Society of Pediatric Oncology. J Clin Oncol 19:1288-1296, 2001. © 2002 by PRR, Inc. All rights reserved.

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